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| Web: | mayocliniclabs.com |
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| Email: | mcl@mayo.edu |
| Telephone: | 800-533-1710 |
| International: | +1 855-379-3115 |
| Values are valid only on day of printing | |
A 67-year-old man with a biopsy-proven gastrointestinal stromal tumor status post-treatment underwent a partial gastrectomy for resection of a persistent mass.
The correct answer is ...
Gastrointestinal stromal tumor with chondroid differentiation.
The patient is a 67-year-old man with a biopsy-proven gastrointestinal stromal tumor status post-treatment who underwent a partial gastrectomy for resection of a persistent mass.
Microscopically, sections of the gastric mass showed two distinct morphologic components. Spindle cells with high nuclear to cytoplasmic ratio, vesicular chromatin, and rare mitoses (Image 2). The second component was composed of mixed spindled and epithelioid cells with chondroid differentiation (Image 3). The second component also showed nuclear pleomorphism, vesicular chromatin, and numerous mitotic figures (greater than 10 mitoses per 5 mm2).
Immunohistochemical stains were performed at the referring institution and Mayo Clinic. The spindle cells were positive for CD34, vimentin, CD117 (patchy), DOG1 (patchy), desmin (patchy), and SMA (patchy). S100 was positive in areas of chondroid differentiation. Immunostains performed at Mayo Clinic showed diffuse positive staining for CD117 and DOG1 in both spindle and epithelioid cells including the area of chondroid differentiation. There was no loss of succinate dehydrogenase B (SDHB) expression.
The morphology and immunohistochemical profile supported the diagnosis of GIST with chondroid differentiation. In light of the patient's history of prior treatment with imatinib, it is inappropriate to use the conventional GIST risk stratification scheme to assess the aggressiveness of the current tumor. Nonetheless, the presence of abundant mitotic figures certainly is indicative of a high-grade sarcoma. Molecular studies were also performed and no mutations were detected in both c-Kit and PDFGR genes.
GISTs with chondroid differentiation have been reported, more often in treated tumors, but rarely seen in treatment-naïve tumors as well. In a similar clinical setting, GISTs can also show other unusual morphology, suggesting differentiation patterns including osseous, muscular, rhabdoid, vascular and undifferentiated/pleomorphic sarcoma types. It is generally believed that the morphologic variance represents a “trans-differentiation” or “dedifferentiation” process. Strictly speaking, dedifferentiation describes the regression of a lineage-specific tumor to a primitive, less specialized state of development and loss of typical immunohistochemical stains. In other words, classic KIT-positive GIST to anaplastic/pleomorphic-type KIT negative tumors. In contrast, trans-differentiation described the conversion of tumor cells to another specialized cell type. Currently, in the GIST literature, the two terms are used variably without a clear distinction by different authors.
Regardless of terminology, the morphologic variance of GISTs poses a real diagnostic challenge in clinical practice. Pathologists must become aware of the process of “trans-” or “de-”differentiation in GISTs given their unusual morphology and often associated aggressive biological behavior, such as metastasis, recurrence and resistance to kinase inhibitor therapy.
GISTs are the most common mesenchymal neoplasm of the gastrointestinal tract, with three classic morphologic types, namely spindle cell predominant, epithelioid cell predominant, and mixed type. Usually, tumor cells show minimal cytological atypia, low proliferation index, and diffuse CD117 and DOG1 expression. In cases with trans-differentiation or dedifferentiation, searching for areas of classical GIST morphology will support your diagnosis. The trans- or de-differentiated component can show different morphological patterns, often with loss of CD117 and DOG1 expression and aberrant immunostaining positivity for other epithelial or mesenchymal differentiation markers like cytokeratin, desmin, etc. Interestingly, CD34 expression may be preserved in the dedifferentiated component in some cases. In this case, the patient’s prior history of GIST and preserved CD117 and DOG1 expression in the tumor cells are helpful to confirm the diagnosis.
It has been hypothesized that trans- or dedifferentiation may be triggered by alternative escape mechanisms besides the activation mutation in GISTs. Therefore, molecular studies are currently advised in cases of these unusual tumors because they might provide critical diagnostic clue and/or therapeutic insights, especially in cases where classic-GIST is not identified. It will likely help to further understand potential alterations of oncogenic pathways related to this phenomenon.
Finally, in practice, to exclude a possibility of GIST with dedifferentiation or trans-differentiation, it is important to adequately sample tumor specimens and search for areas of classic-GIST even if the initial tumor morphology suggests an undifferentiated sarcoma or sarcoma with heterologous elements.
Alessa Aragao, M.D.
Fellow, Surgical Pathology
Mayo Clinic
Zong-Ming (Eric) Chen, M.D., Ph.D.
Consultant, Anatomic Pathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
A 61-year-old homeless man with a past medical history of chronic alcohol abuse was found deceased in his room at a shelter. He was found sitting on a toilet, which contained large amounts of black, tarry blood. During post-mortem examination, diffuse circumferential black-appearing distal esophageal mucosa with no involvement of the gastric mucosa was noted (Image 1). Esophageal histology showed diffuse basophilic and gangrenous mucosal necrosis with deposition of brown and black pigment (Image 2).
The correct answer is ...
Acute esophageal necrosis.
Acute esophageal necrosis (AEN) is a rare and deadly disease that can cause life-threatening esophageal hemorrhage. AEN is associated with poor nutritional status and multiple comorbidities, including alcoholic cirrhosis, binge drinking, diabetic ketoacidosis, and infection. AEN is characterized by circumferential black discoloration of the distal esophagus with underlying friable hemorrhagic tissue with a sharp transition to normal-appearing mucosa at the gastroesophageal junction. Histologically, severe esophageal mucosal necrosis is seen in AEN. Inflammation and partial destruction of adjacent muscle fibers and blood vessel thrombosis or occlusion may also be seen. The pathophysiology is hypothesized to result from a combination of esophageal mucosal injury and microvascular thrombosis.
Although esophageal variceal rupture can cause acute life-threatening gastrointestinal hemorrhage, especially in alcoholic patients, AEN presents with different gross and histologic findings. Large, dilated submucosal veins that protrude into the esophageal lumen and impart a mottled blue discoloration to the mucosa are seen on gross examination. Histologically, dilated, thin-walled veins in the submucosa are seen with overlying mucosal erosion and are more characteristic of esophageal varices.
Although the ingestion of caustic substances can cause severe esophageal damage with mucosal sloughing and black discoloration, this can be distinguished from AEN based on history as well as the presence of oropharyngeal burns.
Although focal or scattered black discoloration of the distal esophagus can be seen in esophageal melanosis, it is associated with underlying chronic esophagitis. Additionally, melanocytes are seen on histology rather than mucosal necrosis.
Edwin Lin, M.D., Ph.D.
Resident, Anatomic and Clinical Pathology
Mayo Clinic
Catherine Hagen, M.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
The patient is a 45-year-old man who presented with a six-month history of progressive rib and spine pain. An MRI demonstrated a 6.4 cm T2 hyperintense expansile mass with patchy peripheral enhancement involving the thoracic cord from the T8-9 interspace level (Image 1). He subsequently underwent resection. Representative images of the histology and immunohistochemistry are below (Images 2-5). Next generation sequencing revealed this tumor harbored an NF1 and ATRX mutation. Chromosomal microarray analysis demonstrated a CDKN2A/CDKN2B homozygous deletion (Image 6).
The correct answer is ...
Anaplastic pilocytic astrocytoma / High-grade astrocytoma with piloid features.
High-grade astrocytoma with piloid features (HGAP) is a new tumor type in the 2021 WHO Classification of CNS Tumors.1 Epidemiologic data is limited, but non-population based case series suggest this tumor type is rare, particularly in the pediatric population, as the median age at diagnosis is 40 years (range: 4-88 years).2-5 These can occur throughout the CNS, but most commonly arise in the cerebellum.2
Histologically, these tumors can vary greatly in appearance, ranging from histologically bland to high-grade. Importantly, these may show elongated, hair-like cytoplasmic processes, at times morphologically resembling pilocytic astrocytoma. The majority of cases demonstrate abnormal vasculature, ranging from hyperplastic to glomeruloid proliferation.1
Given its morphologic heterogeneity, the diagnosis of this tumor type requires assessment of its molecular profile. Three molecular pathways have been identified as drivers for HGAP, and all three are altered simultaneously in approximately 50% of cases.2 These include MAPK pathway activating mutations; deregulation of the retinoblastoma tumor suppressor protein cell cycle pathway (by CDKN2A/ CDKN2B inactivation or CDK4 amplification); and activation of telomer maintenance by ATRX mutations.2 Currently, DNA methylation profiling is required for the definitive diagnosis of HGAP.
Kathryn Eschbacher, M.D.
Fellow, Anatomic Pathology/Neuropathology
Mayo Clinic
Jorge Trejo-Lopez, M.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
A 72-year-old man was evaluated for a six-month history of weight loss, intermittent night sweats, as well as itching on his back. His laboratory workup was significant for a hemoglobin of 9.4 g/dL and tryptase of 150 ng/mL, and a chest CT revealed axillary lymph node enlargement. A lymph node biopsy was obtained and is shown below.
The correct answer is ...
KIT D816V
Systemic mastocytosis is a rare disorder characterized by a clonal proliferation of morphologically and immunophenotypically atypical mast cells. There is a wide range of clinical presentation with an estimated prevalence of approximately 1 in 10,000 persons.1 In the pediatric population, mastocytosis is frequently a cutaneous-limited disease that may regress, whereas in adults, mastocytosis will often manifest as a systemic disease, affecting one or more organs infiltrated by mast cells.2,3 Organ involvement may include, but is not limited to the liver, spleen, gastrointestinal tract, and bone marrow, which contributes to the variability in patient presentation.1,3
Systemic mastocytosis is classified into several subtypes according to the World Health Organization (WHO): 1. Indolent systemic mastocytosis; 2. Smoldering systemic mastocytosis; 3. Systemic mastocytosis with an associated hematological neoplasm; 4. Aggressive systemic mastocytosis; 5. Mast cell leukemia. The most recent diagnostic criteria, set by the WHO in 2016, includes a combination of major and minor criteria encompassing histopathologic, molecular, and chemical analysis.4
Histopathologic evaluation includes identifying the atypical mast cells. The morphologic features of the atypical mast cells include round to fusiform-shaped cells with long polar cytoplasmic processes, irregular lobulated nuclei, and decreased cytoplasmic granules that are often unevenly distributed.5 Immunohistochemical staining of the atypical cells demonstrates expression of tryptase, CD43, and KIT (CD117) with aberrant coexpression of CD25. Occasional aberrant coexpression of CD2 and CD30 has also been reported.3 Interestingly, CD30 expression occurs more frequently and in increasing intensity with more aggressive forms of the disease. Although tryptase is expressed in most cases, its expression level may be low, leading to an incorrect diagnosis.5
Mutations in KIT, which encodes for the receptor tyrosine kinase KIT (CD117), occurs in greater than 90% of cases, with the D816V mutation being the most notable mutation. This gain in function mutation results in uncontrolled proliferation, autonomous growth, and enhanced survival of mast cells.7 Additional associated mutations include the tumor suppressor gene TET2 and N/K-RAS.8
Belinda Galeano, M.D., Ph.D.
Resident, Anatomic and Clinical Pathology
Mayo Clinic
Min Shi, M.D., Ph.D.
Consultant, Hematopathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
A 42-year-old man with a past medical history significant for neurofibromatosis type 2 (NF2) with multiple resections of meningiomas, perineuriomas, schwannomas, and a spinal ependymoma. Spine MRI now shows an expansile intramedullary mass (1.5 x 1.2 x 1.2 cm) centered at C4 with surrounding edema. The lesion has steadily increased in size. Upon resection, the histologic findings are seen in the images.
The correct answer is ...
Mixed schwannoma and spinal ependymoma.
The tumor showed two distinct components. The first component is consistent with a low-grade ependymoma and is highlighted by GFAP. The tumor shows inconspicuous mitotic activity and no microvascular proliferation or necrosis, supporting a CNS grade 2 designation.
The second component is consistent with a schwannoma, which is highlighted by SOX-10. This component was also positive for S100 with Collagen IV highlighting continuous basement membrane.
Overall, the findings are in keeping with a collision tumor representing two distinct neoplasms, both frequently seen in patients with NF 2.
Spinal ependymomas are frequently seen in patients with NF2. A component of this tumor is consistent with an ependymoma. This is supported by histology showing perivascular pseudorosettes, uniform ovoid nuclei, positive GFAP, and negative OLIG2 immunohistochemistry. The second component of this tumor does not fit this morphology or staining pattern, leaving the possibility of a mixed tumor representing an ependymoma and an additional distinct neoplasm.
Schwannomas are associated with NF2. A component of the tumor is consistent with a schwannoma. This is supported by histology showing alternating hypercellular (Antoni A) and hypocellular (Antoni B) areas, palisading nuclei (Verocay bodies), and highlighted by a positive S-100, SOX-10, and Collagen IV immunohistochemistry stain. The other component of this tumor does not fit this morphology or staining pattern, leaving the possibility of a mixed tumor representing an ependymoma and an additional distinct neoplasm.
Although meningiomas can be located throughout the CNS and are associated with NF2, the histology and immunohistochemical staining pattern of this case does not fit that of a meningioma. Meningiomas are negative for both GFAP and SOX-10 and typically express progesterone receptor, SSTR2, and EMA.
Rachel Horton, D.O.
Resident, Anatomic and Clinical Pathology
Mayo Clinic
@RachelHortonDO
Rachael Vaubel, M.D, Ph.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
A 53-year-old man presents with left neck fullness. An ultrasound was performed demonstrating a 1.8 cm left thyroid nodule. The nodule appeared solid and hypoechoic, with macrocalcifications. His thyroid function tests were normal. This prompted an FNA of the nodule, which demonstrated cytologic features suggestive of papillary thyroid carcinoma. The patient underwent left thyroid lobectomy and isthmusectomy.
The correct answer is ...
Hyalinizing trabecular tumor.
Hyalinizing trabecular tumor (HTT) is a rare, follicular, cell-derived thyroid neoplasm with a characteristic trabecular growth pattern and hyalinization. The tumor is solid and circumscribed with a thin, irregular and uneven fibrous connective tissue capsule. Capsular, vascular, or thyroid parenchymal invasion is almost always absent. The tumor has scant to absent colloid. The neoplastic cells are medium to large, polygonal to fusiform. The oval to elongated shaped nuclei are arranged perpendicular to the long axis of the trabeculae and fibrovascular stroma. Prominent nuclear grooves, irregular nuclear contour, and numerous intranuclear cytoplasmic inclusions are usually present. Perinucleolar halos are also common (arrows in image E). Mitotic figures are uncommon. Other findings such as calcospherites (psammoma or calcific bodies) may be present. Chronic lymphocytic thyroiditis may be seen in the surrounding thyroid parenchyma.
HTT is known to share morphological and architectural similarities with paraganglioma and medullary thyroid carcinoma. It also shares the nuclear features of papillary thyroid carcinoma (PTC). By immunohistochemistry, HTT neoplastic cells are positive for TTF-1, thyroglobulin, PXA-8, CK-PAN, and CK7. Although HTT and PTC may show overlapping immunoreactivity for TTF-1, thyroglobulin and PXA-8, the distinctive cell membrane and cytoplasmic reactivity for Ki-67 (MIB-1) (compared to nuclear staining in PTC), and the lack of diffuse positivity for HBME-1 and galectin-3 staining favor HTT. Furthermore, HTT is shown to harbor recurrent PAX8-GLIS1 or PAX8-GLIS3 gene fusions, while negative for BRAF and RAS gene mutations which may be seen in PTC. HTT neoplastic cells show negative immunoreactivity to calcitonin, chromogranin, pCEA, and S100 protein aiding in its differentiation from medullary thyroid carcinoma and paragangliomas (see below).
Medullary thyroid carcinoma is an invasive tumor, often with multiple growth patterns. It lacks colloid. Amyloid can mimic hyalinization but will be Congo red positive. Medullary thyroid carcinoma is positive for calcitonin, chromogranin, keratin, and pCEA, while negative for thyroglobulin.
Papillary thyroid carcinoma has an invasive papillary and possibly follicular growth pattern. Extensive intratrabecular stromal hyalinization is very rare. Overlapping nuclear features such as nuclear grooves and intranuclear cytoplasmic inclusions can be present in both PTC and HTT. PTC is strongly and diffusely immunoreactive with keratin, CK7, thyroglobulin, TTF-1, CK19, HBME-1, galectin-3, and MSG1 (CITED-1). BRAF gene mutations are the most common genetic alterations. PAX8-GLIS3 seen in HTT is not present in PTC.
Paraganglioma: Histology alone may overlap extensively with HTT, although hyalinization is not usually seen in paragangliomas. By immunohistochemistry, paragangliomas are positive for chromogranin, synaptophysin, and S100 protein (sustentacular cells), while the neoplastic cells are negative for keratin.
Mazen Osman, M.B., B.Ch.
Resident, Anatomic and Clinical Pathology
Mayo Clinic
Anja Roden, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
A 60-year-old man with a history of renal failure is admitted for continuous GI bleeds. His Hb is 5.5 mg/dL (low) and his PT is 18 seconds (prolonged). The clinical team decides to treat the patient with 4 units of fresh frozen plasma (FFP) and 4 units of packed red blood cells (pRBCs) over less than 6 hours. The patient became dyspneic and hypertensive. Physical exam revealed jugular venous distension and pulmonary rales. A chest X-ray reveals bilateral pulmonary edema. Clerical check, DAT, and hemolysis check were all negative/unremarkable. The patient underwent diuretics with resolution of the symptoms within 24 hours.
The correct answer is ...
TACO (transfusion-associated circulatory overload).
Examination of the clerical check, DAT, and hemolysis check was negative/unremarkable, making acute hemolytic transfusion less likely. TRALI usually presents with fever, dyspnea, cyanosis, and hypotension, with chest X-ray showing patchy pulmonary infiltrates. In this case, the patient’s chest X-ray did not show patchy pulmonary infiltrates and did not present with fever or hypotension, making TRALI less likely. FNHTRs are typically non-life-threatening reactions which present with fever and chills toward the conclusion of the transfusion. While FNHTR can present with dyspnea and hypotension, the absence of a fever and/or chills makes FNHTR less likely.
Phuong-Lan Nguyen, M.D.
Fellow, Transfusion Medicine
Mayo Clinic
Justin Kreuter, M.D.
Consultant, Transfusion Medicine
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
